The present invention, in some embodiments thereof, relates to methods and devices for treating pathologies associated with neural damage such as neurodegenerative diseases and to methods of administering a protein-of-interest into a brain of a subject, and more particularly, but not exclusively, to intracranial (IC), intracerebroventricular (ICV) or intrathecal administration of T cells.
Alzheimer disease (AD) is currently considered as the leading cause of dementia among older people and accounts for 60-70% of all dementia cases. It is characterized by a progressive loss of neural cell populations and cognitive decline. Every year, 4.6 million new cases of dementia are reported worldwide. By 2050, it is projected that there will be 100 million people with dementia in the world. The disease is identified by the accumulation of amyloid beta (Aβ) in the hippocampal and cortical areas of the brain, often associated with neurofibrillary tangles caused by hyperphosphorylation of the cytoskeleton protein Tau. The involvement of the immune system in the development and progression of neurodegenerative diseases in general and in AD in particular, is now widely accepted and demonstrated in numerous studies (McGeer, P. L., and E. G. McGeer. 2006; McGeer, P. L., et al., 2006). However, the conventional immunotherapy approaches for AD had only limited clinical results.
Neurogenesis is an intense and dynamic process that maintains the proliferation, migration, and maturation of new neurons. The adult brain contains neural stem cells (NSCs) that self-renew, proliferate and give rise to neural progenitor cells (NPCs) that exhibit partial lineage-commitment. The NSCs differentiate into three major types of central nervous system (CNS) cells: neurons, astrocytes, and oligodendrocytes. Two neurogenic areas are present in the adult brain: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, known as the neurogenic niche. With aging, the proliferation and differentiation of NPCs are significantly suppressed, primarily in the DG. It is suggested that the microenvironment of the SVZ and DG provides special conditions which support neurogenesis. Another aspect that may negatively affect neurogenesis is the reduced level of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and IGF-1/IGF-2 in the neurogenic niche. BDNF was shown to increase the strength of potentiated synapses and also to promote survival and differentiation of Neural stem cells (NSCs).
Neurogenesis was found to be increased in the brains of patients with AD compared to age-matched control subjects, suggesting that there are mechanisms in the brain directed to overcoming the loss of function. In contrast, different mouse models of AD have shown either reduced or enhanced neurogenesis in the dentate gyrus (DG).
In recent years accumulated evidences have indicated that the neurogenic process is negatively and positively affected by the immune system (Ziv Y, et al. Nat Neurosci. 2006, 9: 268-75; Butovsky O, et al. Mol Cell Neurosci. 2006, 31: 149-60; Baron R, et al. FASEB J. 2008, 22: 2843-52; Aharoni R, et al. J. Neurosci. 2005, 25: 8217-28). In particular, the role of CD4+ T cells in neurogenesis has created considerable interest in light of findings demonstrating that auto-antigen-specific T cells are key players in functional recovery of injured neurons.
It is now believed that the central nervous system (CNS) is not immune privileged and that there is important cross-talk between the CNS and immune cells which is crucial for CNS maintenance and repair. Nonetheless, in slowly progressing diseases of the ageing brain, the immune response required for tissue repair is impaired and needs proper stimulation. It has been shown that in acute CNS damage administration of ex-vivo activated macrophages enhances healing (Shechter, R., A. et al., 2009). This is partially due to the fact that in various acute instances, failure of the blood brain barrier (BBB) enables immune cellular components to infiltrate into the brain. It has been shown that following acute injury to the CNS, certain lymphocytes migrate into the brain and promote recovery (Moalem, G., et al., 1999. Differential T cell response in central and peripheral nerve injury: connection with immune privilege. Faseb J 13:1207-1217).
Various studies showed that migration of peripheral immune components to the CNS can be dangerous. Thus, clinical trials showed that immunization with Aβ is associated with menigoencephalitis (Orgogozo, J. M., et al., 2003. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61:46-54.). In addition, immunization of mice with Aβ is associated with entry of cytotoxic CD8 T cells, and brain hemorrhages caused by Aβ antibodies (Gandy, S., and L. Walker. 2004. Toward modeling hemorrhagic and encephalitic complications of Alzheimer amyloid-beta vaccination in nonhuman primates. Curr Opin Immunol 16:607-615; Pfeifer, M., et al. 2002. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 298:1379).
Monsonego, A., J. et al., 2006 (Abeta-induced meningoencephalitis is IFN-{gamma}-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 103:5048-5053) show that infiltration of T lymphocytes into the CNS in the presence of low level of expression of IFNγ following Aβ immunization of humanized AD Tg-mice is accompanied by meningocephalitis. These T lymphocyte cells specifically targeted Aβ plaques and consequently enhance their removal (Fisher, Y., A. Nemirovsky, R. Baron, and A. Monsonego. T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease. PLoS One 5:e10830).
U.S. Patent Application No. 20030108528 (Eisenbach-Schwartz, Michal, et al.) describes a method of treating injury or disease of the central nervous system using non-recombinant activated antiself T-cells that recognize an antigen of the nervous system (NS) or a peptide derived therefrom to promote nerve regeneration or to prevent or inhibit axonal degeneration within the NS.
U.S. Patent Application No. 20040253218 (Eisenbach-Schwartz, Michal, et al.) describes methods of promoting nerve regeneration, conferring neuroprotection and preventing neuronal degeneration within the nervous system by administering a nervous system-specific activated T cells, or a nervous system-specific antigen.
U.S. Patent Application No. 20050123553 (Monsonego, Alon et al.) describes novel compositions containing an amyloid beta peptide and methods of using these compositions for treating and preventing Aβ-protein related (e.g., an amyloid fibril) disorders such as Alzheimer's disease.
U.S. Patent Application No. 20100144868 (Gozin; Michael et al.) describes hybrid compounds having a fullerene core residue, bioavailability enhancing moieties and glutamate receptor ligand residues, whereby the bioavailability enhancing moiety allows the compound to reach an effective concentration in physiological media and pass the blood-brain barrier for the treatment of medical conditions associated with oxidative stress and/or neural damage, such as, for example, neurological diseases, disorders and trauma.
WO 2009/081395 (Monsonego A) describes compositions and methods for treating a subject suffering from a disease of the nervous system, associated with an inflammatory response, the compositions include an agent which increases brain levels of interferon-γ; and an agent which reduces the number of brain T regulatory (Treg) cells, and optionally an agent which suppresses neurotoxic inflammatory brain responses.
CD4 T cells are divided into several sub-populations, characterized by their cytokine secretion profile and their roles in immunity. The most common sub-populations are the Th1, Th2 and Th17 T cells. Th1 cells are inflammatory cells secreting the growth factor IL-2 and the effector cytokine IFN-γ. These cells are known for their role in macrophage stimulation, enhancing their phagocyte activity. Th2 cells are anti-inflammatory cells secreting the growth factors IL-2 and IL-4 and the effector cytokines IL-10 and TGFβ known also as regulatory cytokines. Th2 cells are best known for their role in supporting antibody production from plasma cells. Th17 cells were only recently characterized and they are classified by IL-17A as their effector cytokine. They have been shown to be highly proinflammatory cells and function in eliminating large extra-cellular parasites mainly by recruiting neutrophils.
Monsonego, A. et al., 2003 (Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 112:415-422) describe a remarkably increased frequency of Aβ-specific T cells in healthy older individuals and in patients with AD.
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